14-dehydro progesterone and intermediates in the production thereof



United States This invention relates to a novel process for reducingsteroid-14: 16-dienes.

It is known that steroid-14:16-dienes when subjected to catalyticreduction yield l4-iso-17-iso-steroids, that is to say steroids having aconfiguration in the 14- and 17- position which does not correspond tothe normal configuration for the corresponding natural substances.

An object of the present invention is to provide a proc ess for thereduction of steroid-14:16-dienes to form 14- dehydro-steroids havingthe normal configuration in the l7-position. These compounds can behydrogenated in known manner to steroids with a normal configuration inthe l t-position. The novel process comprises reducingsteroid-14:16-dienes by treatment with nascent hydrogen.

In carrying out the process, the nascent hydrogen is advantageouslyformed by the reaction of an alkali metal or an alkaline earth metal,especially lithium, but also sodium, potassium, calcium or an alkalimetal amalgam, with an alcohol alone and/or a nitrogen base. Among thealcohols there may be mentioned aliphatic alcohols, such as methanol,ethanol, propanol, isopropanol, butanol, amyl alcohol or the like. Asnitrogen bases there are especially suitable ammonia, and also aliphaticamines, such as methylamine, ethylamine, propylamine, ethylene diamine,either alone or in combination with one another.

When the reduction is carried out with the above mentioned metals and analcohol alone, it is of advantage to work at a raised temperature, forexample, between 30 and 100 C. When the reduction is carried out with avolatile nitrogen base, low temperatures must be maintained, in the caseof ammonia about 40 C., or it may be carried out under superatmosphericpressure and at a higher temperature, for example, at room temperature.

In accordance with the invention the reduction is advantageously carriedout in the presence of an organic solvent, such as ether, for example,diethyl ether, dimethoxy-ethane, dioxane, a hydrocarbon, for example,petroleum ether, toluene or the like.

As starting materials there are suitable steroid-14:16- dienes obtainedfrom natural steroids or those obtained by total synthesis, that is tosay optically active or racemic steroid-14:16-dienes, and also thecorresponding compounds of the 19-nor-and/ or D-homo-series. Especiallyimportant are the starting materials having a free or functionallyconverted acetyl, oxyacetyl or carboxyl group in the 7-position, andwhich contain in the 3-, 11- and/or Iii-position a free or functionallyconverted hydroxyl or x0 group, for example, an esterified or etherifiedhydroxyl group or an acetalized oxo group and/ or further double bonds,such as a double bond starting from the S-carbon atom, that is to say inthe 4:5- or 5 :6-position. The hydroxyl groups in the functionallyconverted oxyacetyl radical are present in esterified or etherifiedform. As a functionally converted carboxyl group there may be mentionedmore especially an esterified carboxyl group, but also for example, acidamide or nitrile groups. Such starting materials are known or can bemade by the methods described in specifications Nos. 480,061, filedJanuary 5, 1955, by T. Reichstein et al., 480,062, filed January 5,1955, by T. Reichstein et al., 485,324, filed atent ice January 31,1955, by Wettstein et al., 485,326, filed January 31, 1955, by Wettsteinet al., now Patent No. 2,883,378.

Groups which are capable of being reduced under the conditions of thepresent process, for example, oxo groups, may be protectedintermediately, especially by conversion into acetalized oxo groups, ormay be simultaneously reduced, for example, 0x0 to hydroxyl groups.Hydroxyl groups can be reconverted to 0x0 groups by the knowndehydrogenation methods.

The products of this invention are of therapeutic value and can be usedas medicaments, as far as they have the configuration and substituentsof therapeutically valuable steroids, for example the14-dehydroprogesterone which has a progestational effect and can be usedas a medicament for the treatment of corpus luteum deficiency. Theproducts of the invention are also useful as intermediate products. Asmentioned above, they can be converted into the corresponding steroidswith normal configuration in 14-position, for example the14-dehydroprogesterone into progesterone by the following scheme ofreactions:

O O The following examples illustrate the invention the parts being byweight unless otherwise stated, and the relationship of parts by weightto parts by volume being the same as that of the gram to the cubiccentimeter:

Example 1 1 part of pure A -3fi-hydroxy-ZO-oxo-pregnatriene melting at186l87 C. is dissolved in a mixture of 40 parts by volume of dioxane and40 parts by volume of ether, and the solution is introduced dropwisewith the exclusion of moisture at -40 C. to -50 C. with vigorous mixinginto a solution of 1.25 parts of lithium in 600 parts by volume ofliquid ammonia. After one hour there are added to the reaction mixturedrop by drop 55 parts by volume of n-propanol. After the addition of 1part of lithium the reaction mixture is stirred for a further /2 hourand then poured on to ice.

The mixture is worked up by extraction with ether to yield 1 part of acrude reduction product which is oxidized in known manner in benzenesolution with aluminum tertiary butylate and cyclohexanone as follows:One part of the crude reduction product is dissolved in 25 parts byvolume of benzene and 25 parts by volume of cyclohexanone and after theaddition of one part of aluminum tertiary butylate refluxed for 10hours. The reaction mixture is cooled, treated with water, filtered andthe solvents are distilled oflf in vacuo. As it is known that20-oxo-pregnane derivatives when oxidized by the Oppenauer method oftenyield non-unitary reaction products, it is recommended to subject thecrude product to an after-oxidation with chromium trioxide (0.85 part)in 3 pyridine (25 parts by volume) at 20 C. Working up in the normalmanner by pouring the reaction mixture into water and extracting with amixture of benzene and ether (1:1) yields a crude product from whichl4-dehydro-progesterone is obtained by chromatographic puri fication(0.3 part), which crystallizes from hexane in coarse prisms melting at127-128 C.

By further recrystallization the melting point is raised to 134 C. Theconstitution of this compound can be shown by the following conversions:

By reducing the 14-dehydroprogesterone in the manner described abovewith lithium, ammonia and n-propanel and after-oxidizing, for example bymeans of pyridine chromic acid complex as described above, the A 3;20dioxo allopregnene melting at 186-187 C.; [m] =+78 (in chloroform) isobtained, which can also be obtained from the known A-3B-acetoxy-20-oxopregnene by hydrolysis and oxidation with pyridinechromic acid complex or according to Oppenauers method.

Example 2 1 part of pure A -3B-hydroxy-2O-oxo-pregnatriene melting at186-187 C., maximum=3l0 m (log a: 4.14), is dissolved in a mixture of 20parts by volume of dioxane and 20 parts by volume of ether and addeddropwise with the exclusion of moisture and vigorous mixing at 45 C. toa solution of 0.13 part of lithium in 300 parts by volume of liquidammonia. After one hour n-propanol is added dropwise to the reactionmixture until the solution loses color. After adding 0.03 part oflithium the reaction mixture is stirred for a further 30 minutes, thenn-propanol is once more added until the solution loses color, whereuponthe two last operations (addition of lithium and discoloration withn-propanol) are repeated once again.

Working up is carried out by evaporation of the ammonia, whereupon thereaction mixture is neutralized at given in Example 1 leads to14-dehydroprogesterone melting at 134 C. The compound exhibits in theultraviolet spectrum an absorption maximum at 242 In (log=4.2).

Example 3 0.37 part of A -3fi-hydroxy-20-oxo-pregnatriene is dissolvedin parts by volume of n-propanol. To the with 2 N-sulfuric acid. Themixture is worked up by V extraction with ether to yield 1 part of acrude product from which there are isolated by chromatographicpurification over aluminum oxide and fractionated crystallization frommethanol the A -3 3;2Oa-dihydroxy-preg nadiene melting at 218-220" C.and the A -3/3;20fi dihydroxy-pregnadiene melting at 214-215 C. The3g20-diacetate of the first compound is prepared with acetic anhydrideand pyridine and melts at 178-179 C. [u] =3Z (CHClg); the isomericdiacetate also melts at 178-179"; [u] =10 (CHCl The two compounds showin a mixed melting point test a lowering of the melting point of about20 C.

The oxidation of the epimeric A -3/3;20-dihydroxypregnadienes at carbonatom 20 according to Oppenauers method in benzene with aluminum tertiarybutylate and cyclohexanone followed by an after-oxidation with chromiumtrioxide in pyridine according to the details boiling solution there isadded in the course of 30 minutes 0.4 part of clean sodium shavings.After a further 40 minutes all of the sodium has reacted. The cooledreaction mixture is poured into Water, extracted with ether and theether evaporated after Washing and drying. By chromatographic separationover aluminum oxide and fractionated crystallization from methanol thereare isolated the A -35g2Oa-dihydrOXY-pregnadiene melting at 2l8-220 C.,and the A -35:2Ofi-dihydroxy-pregnadine melting at 214-215 C.

What is claimed is:

l. A process which comprises hydrogenating a 20- keto-14:l6-pregnadieneby contacting it with a member of the group consisting of an alkalimetal and an alkaline earth metal in the presence of a member of thegroup consisting of a lower alkanol, ammonia, primary lower alkylamines,and mixtures thereof, and isolating the correspondin14-dehydro-pregnenes oxygenated at position 20 and having the normalconfiguration in the 17-position.

2. A process as claimed in claim 1, in which the hydrogenation withlithium is carried out in the presence of a mixture of ammonia andpropanol.

3. A process as claimed in claim 1, in which an 0x0 group in the20-keto-l4: lo-pregnadiene is simultaneously reduced to a hydroxylgroup.

4. A process as claimed in claim 3, which comprises dehydrogenating thehydroxyl groups in compounds obtained to oxo groups.

5. A non-catalytic process which comprises hydrogenating A -3,B-hydroxyZO-oxopregnatriene by contact with nascent hydrogen and recovering thecorresponding 14-dehydro-pregnadiene having the normal configuration inthe l7-position.

6. A process in accordance with claim 5, wherein hydroxyl groups in thehydrogenation product are dehydrogenated so as to producel4-dehydroprogesterone.

7. A -3510a-dihydroxy-pregnadiene.

8. A -3,8,20B-dihydroxy-pregnadiene.

9. 14-dehydroprogesterone 10. A non-catalytic process which comprisestreating 20-keto-l4:l6-pregnadienes with nascent hydrogen and recoveringthe corresponding l4-dehydro-pregnenes having the normal configurationin the 17-position.

References Cited in the file of this patent Kendal: Smiths InorganicChemistry, 2nd edition, pages 534-5 (1937).

Plattner: Helv. Chim. Acta, 31, 249-56 (1948).

1. A PROCESS WHICH COMPRISES HYDROGENATING A 20KETO-14:16-PREGNADIENE BYCONTACTING IT WITH A MEMBER OF THE GROUP CONSISTING OF AN ALKALI METALAND AN ALKALINE EARTH METAL IN THE PRESENCE OF A MEMBER OF THE GROUPCONSISTING OF A LOWER ALKANOL, AMMONIA, PRIMARY LOWER ALKYLAMINES, ANDMICTURES THEREOF, AND ISOLATING THE CORRESPONDING 14-DEHYDRO-PREGNESESOXYGENATED AT POSITION 20 AND HAVING THE NORMAL CONFIGURATION IN THE17-POSITON.
 8. *5-14-3B,20B-DIHYDROCXY-PREGNDIENE.